Aytenfisu Asaminew H, Simon Raphael, MacKerell Alexander D
University of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, 21201, United States.
Center for Vaccine Development, Institute for Global Health, School of Medicine, University of Maryland, Baltimore, MD, 21201, United States.
Carbohydr Res. 2019 Mar 1;475:39-47. doi: 10.1016/j.carres.2019.02.003. Epub 2019 Feb 18.
Resistance of Klebsiella pneumoniae (KP) to antibiotics has motivated the development of an efficacious KP human vaccine that would not be subject to antibiotic resistance. Klebsiella lipopolysaccharide (LPS) associated O polysaccharide (OPS) types have provoked broad interest as a vaccine antigen as there are only 4 that predominate worldwide (O1, O2a, O3, O5). Klebsiella O1 and O2 OPS are polygalactans that share a common D-Gal-I structure, for which a variant D-Gal-III was recently discovered. To understand the potential impact of this variability on antigenicity, a detailed molecular picture of the conformational differences associated with the addition of the D-Gal-III (1 → 4)-α-Galp branch is presented using enhanced-sampling molecular dynamics simulations. In D-Gal-I two major conformational states are observed while the presence of the 1 → 4 branch in D-Gal-III resulted in only a single dominant extended state. Stabilization of the more folded states in D-Gal-I is due to a O4-H⋯O2 hydrogen bond in the linear backbone that cannot occur in D-Gal-III as the O4 is in the Galp(1 → 4)Galp glycosidic linkage. The impact of branching in D-Gal-III also significantly decreases the accessibility of the monosaccharides in the linear backbone region of D-Gal-I, while the accessibility of the terminal D-Gal-II region of the OPS is not substantially altered. The present results suggest that a vaccine that targets both the D-Gal-I and D-Gal-III LPS can be developed by using D-Gal-III as the antigen combined with cross-reactivity experiments using the Gal-II polysaccharide to assure that this region of the LPS is the primary epitope of the antigen.
肺炎克雷伯菌（KP）对抗生素的耐药性促使人们研发一种有效的KP人用疫苗，这种疫苗不会受到抗生素耐药性的影响。肺炎克雷伯菌脂多糖（LPS）相关的O多糖（OPS）类型作为疫苗抗原引起了广泛关注，因为在全球范围内只有4种占主导地位（O1、O2a、O3、O5）。肺炎克雷伯菌O1和O2 OPS是共享常见D-Gal-I结构的聚半乳糖，最近发现了其变体D-Gal-III。为了了解这种变异性对抗原性的潜在影响，使用增强采样分子动力学模拟展示了与添加D-Gal-III（1→4）-α-Galp分支相关的构象差异的详细分子图景。在D-Gal-I中观察到两种主要构象状态，而D-Gal-III中1→4分支的存在仅导致一种单一的优势伸展状态。D-Gal-I中更折叠状态的稳定是由于线性主链中的O4-H⋯O2氢键，而在D-Gal-III中由于O4处于Galp（1→4）Galp糖苷键中，这种氢键无法形成。D-Gal-III中分支的影响还显著降低了D-Gal-I线性主链区域中单糖的可及性，而OPS末端D-Gal-II区域的可及性没有实质性改变。目前的结果表明，通过使用D-Gal-III作为抗原并结合使用Gal-II多糖的交叉反应实验来确保LPS的该区域是抗原的主要表位，可以开发出针对D-Gal-I和D-Gal-III LPS的疫苗。
